Gruber, Kenneth A. Cachexia-anorexia syndrome is a life-threatening aspect to many diseases, in particular many forms of cancer or therapies for cancer. The obvious symptoms of this disease include lack of appetite, and a loss of lean body mass disproportionate to the reduction in caloric intake. However, the less obvious effects of cachexia include multi-organ failure, due to high metabolic rate-induced apoptosis (programmed cell death). The economic costs of cachexia are huge. The National Cancer Institute estimates that up to 40% of cancer deaths are directly due to cachexia, and it is likely a factor in a significant percent of other cancer fatalities. Cachexia is a component in the pathology of many other diseases. Hyperactivity of the central melanocortin (MC) system appears to be a common factor in most, if not all, forms of cachexia We designed and synthesized a MC drug-like peptide (TCMCB07), using a new platform technology that makes peptides into therapeutic agents with an extended in vivo half-life. TCMCB07 produced a reversal of cachexia in an aggressive experimental cancer model; restoring food intake and lean body mass. The ability of TCMCB07 to enhance weight gain has been confirmed in large animal models. Preliminary safety testing has shown that the drug is relatively free of cardiovascular, blood chemistry or hematological side-effects. The goals of this application are to perform the required preclinical experiments to establish the relative safety and efficacy of our anticachexia therapeutic, and define its interactions with cellular transport systems. Delineating the transport system(s) for TCMCB07 will allow a determination of its potential interaction with other clinically relevant drugs. The overall objective of these experiments is the submission of an Investigative New Drug application to the FDA for an anticachexia drug, a required step before Phased Clinical Trials. Preventing or reversing cachexia has the potential to enhance the efficacy of current and future anticancer agents, as well as be an important therapeutic component in the treatment of many other life-threatening diseases.